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2.
BMC Med Genet ; 21(1): 35, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066420

RESUMO

BACKGROUND: We report a large family with four successive generations, presenting with a complex phenotype of severe congenital neutropenia (SCN), partially penetrant monocytosis, and hearing loss of varying severity. METHODS: We performed whole exome sequencing to identify the causative variants. Sanger sequencing was used to perform segregation analyses on remaining family members. RESULTS: We identified and classified a pathogenic GFI1 variant and a likely pathogenic variant in MYO6 which together explain the complex phenotypes seen in this family. CONCLUSIONS: We present a case illustrating the benefits of a broad screening approach that allows identification of oligogenic determinants of complex human phenotypes which may have been missed if the screening was limited to a targeted gene panel with the assumption of a syndromic disorder. This is important for correct genetic diagnosis of families and disentangling the range and severity of phenotypes associated with high impact variants.


Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea/genética , Proteínas de Ligação a DNA/genética , Perda Auditiva Neurossensorial/genética , Cadeias Pesadas de Miosina/genética , Neutropenia/congênito , Fatores de Transcrição/genética , Adulto , Idoso , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/fisiopatologia , Exoma/genética , Feminino , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/fisiopatologia , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Neutropenia/complicações , Neutropenia/diagnóstico , Neutropenia/genética , Neutropenia/fisiopatologia , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
3.
Cytogenet Genome Res ; 160(1): 11-17, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31982875

RESUMO

Small supernumerary marker chromosomes (sSMCs) are characterized as additional centric chromosome fragments which are too small to be classified by cytogenetic banding alone and smaller than or equal to the size of chromosome 20 of the same metaphase spread. Here, we report a patient who presented with slight neutropenia and oral aphthous ulcers. A mosaic de novo sSMC, which originated from 5 discontinuous regions of chromosome 8, was detected in the patient. Formation of the sSMC(8) can probably be explained by a multi-step process beginning with maternal meiotic nondisjunction, followed by post-zygotic anaphase lag, and resulting in chromothripsis. Chromothripsis is a chromosomal rearrangement which occurs by breakage of one or more chromosomes leading to a fusion of surviving chromosome pieces. This case is a good example for emphasizing the importance of conventional karyotyping from PHA-induced peripheral blood lymphocytes and examining tissues other than bone marrow in patients with inconsistent genotype and phenotype.


Assuntos
Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 8/ultraestrutura , Neutropenia/genética , Úlceras Orais/genética , Estomatite Aftosa/genética , Pré-Escolar , Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Citogenética , Feminino , Marcadores Genéticos , Genótipo , Humanos , Cariotipagem , Linfócitos/metabolismo , Metáfase , Mosaicismo , Neutropenia/complicações , Neutropenia/diagnóstico , Análise de Sequência com Séries de Oligonucleotídeos , Úlceras Orais/complicações , Úlceras Orais/diagnóstico , Fenótipo , Estomatite Aftosa/complicações , Estomatite Aftosa/diagnóstico
4.
Acta otorrinolaringol. esp ; 70(6): 348-357, nov.-dic. 2019. tab, graf, ilus
Artigo em Espanhol | IBECS | ID: ibc-184880

RESUMO

Antecedentes y objetivo: El objetivo del estudio ha sido describir los resultados del tratamiento de sinusitis fúngica invasiva con cirugía endoscópica nasal en una población oncológica pediátrica con inmunosupresión e informar sobre la seguridad, la eficacia y las complicaciones del procedimiento. Métodos: Se realizó un estudio retrospectivo de la totalidad de los pacientes con diagnóstico de sinusitis fúngica invasiva operados en la Unidad Nacional de Oncología Pediátrica entre los años 2012 y 2016. Los datos tomados de su historial médico incluyeron: características epidemiológicas, diagnóstico oncológico, datos hematológicos, síntomas, estudios tomográficos, intervenciones quirúrgicas, resultados de enfermedad y cultivos, medicamentos recibidos, complicaciones, evolución y supervivencia. Los datos fueron analizados utilizando estadística descriptiva, las variables continuas con medidas de tendencia central y las variables categóricas de forma porcentual. Resultados: Se identificó a 18 pacientes, 7 de sexo masculino y 11 de sexo femenino. El promedio de edad fue de 12 años, 13 tuvieron diagnóstico de leucemia linfoide aguda y 5 de leucemia mieloide aguda; 17 pacientes presentaron neutropenia severa en el momento del diagnóstico. El agente etiológico más frecuentemente identificado fue Aspergillus en 13 pacientes. En 16 pacientes (89%) se controló la enfermedad con cirugía endoscópica nasal. Diez pacientes fallecieron por causas no relacionadas a lo largo del estudio. Discusión y conclusiones: La sinusitis fúngica invasiva es una enfermedad cuya incidencia va en aumento entre pacientes con inmunosupresión y debe de considerarse una urgencia médica debido a su alta mortalidad. El diagnóstico se basa en un alto índice de sospecha en pacientes con factores predisponentes (leucemia, neutropenia, fiebre persistente, sonda nasogástrica) y la evaluación endoscópica nasal. El tratamiento médico antifúngico y cirugía endoscópica nasal agresiva está indicado independientemente del estado del paciente para disminuir la carga fúngica y la alta mortalidad asociada. El tratamiento debe de ser suministrado por un equipo multidisciplinario que incluye pediatría, hemato-oncología, infectología y otorrinolaringología


Background and objective: to describe the results of the treatment of invasive fungal sinusitis with nasal endoscopic surgery in an immunocompromised paediatric oncological population. Methods: retrospective study of all patients diagnosed with invasive fungal sinusitis operated in the National Paediatric Oncology Unit between 2012 and 2016. Data taken from their medical history included: epidemiological characteristics, oncological diagnosis, haematological data, symptoms, tomographic studies, surgical interventions, results of pathology and cultures, medications received, complications, evolution and survival. Results: 18 patients were identified, 7 male and 11 female. The average age was 12 years, 13 had a diagnosis of acute lymphocytic leukemia and 5 of acute myeloid leukemia. Seventeen patients presented severe neutropenia at the time of diagnosis. The most frequently identified aetiological agent was Aspergillus in 13 patients. In 16 patients (89%) the disease was controlled with nasal endoscopic surgery. Ten patients died due to unrelated causes throughout the study. Discussion and conclusions: Invasive fungal sinusitis should be considered a medical emergency due to its high mortality. The diagnosis is based on a high index of suspicion in patients with predisposing factors (leukaemia, neutropenia, persistent fever, nasogastric tube) and endoscopic nasal evaluation. Antifungal medical treatment and aggressive nasal endoscopic surgery is indicated regardless of the patient's condition to reduce the fungal burden and associated high mortality. The treatment must be provided by a multidisciplinary team that includes paediatrics, haemato-oncology, infectology and otorhinolaryngology


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Sinusite/diagnóstico , Sinusite/cirurgia , Imunossupressão , Endoscopia/métodos , Avaliação de Resultado de Intervenções Terapêuticas , Estudos Retrospectivos , Neutropenia/complicações , Aspergillus/isolamento & purificação , Micoses/complicações , Febre/etiologia , Seios Paranasais/diagnóstico por imagem , Complicações Pós-Operatórias
5.
BMC Med Genet ; 20(1): 182, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727123

RESUMO

BACKGROUND: Majeed syndrome is a rare, autosomal recessive autoinflammatory disorder first described in 1989. The syndrome starts during infancy with recurrent relapses of osteomyelitis typically associated with fever, congenital dyserythropoietic anemia (CDA), and often neutrophilic dermatosis. Mutations in the LPIN2 gene located on the short arm of chromosome 18 have been identified as being responsible for Majeed syndrome. CASE PRESENTATION: We report an 8-month-old boy, who presented with recurrent fever, mild to moderate anemia, and severe neutropenia. Erythrocyte sedimentation rate and C-reactive protein were elevated. Molecular testing identified a paternal splicing donor site variant c.2327 + 1G > C and a maternal frameshift variant c.1691_1694delGAGA (Arg564Lysfs*3) in LPIN2. CONCLUSIONS: Only a few cases with LPIN2 mutation have been reported, mainly in the Middle East with homozygous variants. Our patient exhibited a mild clinical phenotype and severe neutropenia, different from previous reports.


Assuntos
Anemia Diseritropoética Congênita/genética , Febre/complicações , Síndromes de Imunodeficiência/genética , Mutação , Neutropenia/complicações , Proteínas Nucleares/genética , Osteomielite/genética , Anemia Diseritropoética Congênita/complicações , Feminino , Humanos , Síndromes de Imunodeficiência/complicações , Lactente , Masculino , Osteomielite/complicações , Linhagem , Recidiva , Índice de Gravidade de Doença
6.
JAMA ; 322(17): 1673-1681, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31688884

RESUMO

Importance: Children, adolescents, and young adults with acute myeloid leukemia are at high risk of life-threatening invasive fungal disease with both yeasts and molds. Objective: To compare the efficacy of caspofungin vs fluconazole prophylaxis against proven or probable invasive fungal disease and invasive aspergillosis during neutropenia following acute myeloid leukemia chemotherapy. Design, Setting, and Participants: This multicenter, randomized, open-label, clinical trial enrolled patients aged 3 months to 30 years with newly diagnosed de novo, relapsed, or secondary acute myeloid leukemia being treated at 115 US and Canadian institutions (April 2011-November 2016; last follow-up June 30, 2018). Interventions: Participants were randomly assigned during the first chemotherapy cycle to prophylaxis with caspofungin (n = 257) or fluconazole (n = 260). Prophylaxis was administered during the neutropenic period following each chemotherapy cycle. Main Outcomes and Measures: The primary outcome was proven or probable invasive fungal disease as adjudicated by blinded central review. Secondary outcomes were invasive aspergillosis, empirical antifungal therapy, and overall survival. Results: The second interim efficacy analysis and an unplanned futility analysis based on 394 patients appeared to have suggested futility, so the study was closed to accrual. Among the 517 participants who were randomized (median age, 9 years [range, 0-26 years]; 44% female), 508 (98%) completed the trial. The 23 proven or probable invasive fungal disease events (6 caspofungin vs 17 fluconazole) included 14 molds, 7 yeasts, and 2 fungi not further categorized. The 5-month cumulative incidence of proven or probable invasive fungal disease was 3.1% (95% CI, 1.3%-7.0%) in the caspofungin group vs 7.2% (95% CI, 4.4%-11.8%) in the fluconazole group (overall P = .03 by log-rank test) and for cumulative incidence of proven or probable invasive aspergillosis was 0.5% (95% CI, 0.1%-3.5%) with caspofungin vs 3.1% (95% CI, 1.4%-6.9%) with fluconazole (overall P = .046 by log-rank test). No statistically significant differences in empirical antifungal therapy (71.9% caspofungin vs 69.5% fluconazole, overall P = .78 by log-rank test) or 2-year overall survival (68.8% caspofungin vs 70.8% fluconazole, overall P = .66 by log-rank test) were observed. The most common toxicities were hypokalemia (22 caspofungin vs 13 fluconazole), respiratory failure (6 caspofungin vs 9 fluconazole), and elevated alanine transaminase (4 caspofungin vs 8 fluconazole). Conclusions and Relevance: Among children, adolescents, and young adults with acute myeloid leukemia, prophylaxis with caspofungin compared with fluconazole resulted in significantly lower incidence of invasive fungal disease. The findings suggest that caspofungin may be considered for prophylaxis against invasive fungal disease, although study interpretation is limited by early termination due to an unplanned interim analysis that appeared to have suggested futility. Trial Registration: ClinicalTrials.gov Identifier: NCT01307579.


Assuntos
Antifúngicos/uso terapêutico , Caspofungina/uso terapêutico , Fluconazol/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Micoses/prevenção & controle , Adolescente , Adulto , Antifúngicos/efeitos adversos , Aspergilose/epidemiologia , Aspergilose/prevenção & controle , Caspofungina/efeitos adversos , Criança , Pré-Escolar , Término Precoce de Ensaios Clínicos , Feminino , Fluconazol/efeitos adversos , Humanos , Lactente , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/complicações , Masculino , Neutropenia/complicações , Adulto Jovem
7.
Medicine (Baltimore) ; 98(39): e17372, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574885

RESUMO

INTRODUCTION: Cyclic neutropenia (CyN) is a rare hematological disease, and patients with CyN often experience an early onset of severe periodontitis and are forced to undergo tooth extraction. Here, we report a case of a patient with CyN who showed different periodicity and oscillations of neutrophil count compared with her mother, despite sharing the same novel genetic mutation. PATIENT CONCERNS: A 17-year-old Japanese girl who had been diagnosed with CyN shortly after birth presented to our hospital with a complaint of mobility of her teeth and gingivitis. Upon presentation, an intraoral examination was performed and revealed redness and swelling of the marginal and attached gingiva. Radiographs revealed extreme resorption of the alveolar bone and apical lesions in her mandibular lateral incisors. The patient's hematologic data demonstrated a lack of blood neutrophils (0/µL). The patient had no history of dental extraction, and her mother also had a history of CyN. DIAGNOSES: The patient was diagnosed with severe periodontitis that was associated with CyN. Gene testing showed a novel heterozygous mutation in exon 4 of the ELANE gene (c.538delC, p.Leu180Ser fsX11). INTERVENTIONS: Based on the clinical findings, we planned to extract the patient's mandibular lateral incisors. Although the tooth extraction was scheduled considering the cyclic variation in neutrophil count, the patient's neutrophil count was 0/µL on the day before the planned extraction. Therefore, granulocyte-colony stimulating factor (G-CSF) was administered to increase the patient's neutrophil count. On the day of the patient's admission for the tooth extraction, she presented with fever (body temperature, 38.5°C), tonsillitis, and stomatitis. The extraction was subsequently delayed, and the patient was administered antibiotics and G-CSF for 4 days. At this time, the neutrophil count increased to 750/µL, and the tooth extraction was carried out safely. OUTCOMES: The postoperative course was uneventful, and the healing process at the extraction site was excellent. CONCLUSION: There is a possibility that the periodicity and oscillations of neutrophil count may change with growth in patients with CyN. Therefore, it is important to frequently examine and treat patients with fluctuating neutrophil levels for the management of invasive dental treatment in patients with CyN.


Assuntos
Elastase de Leucócito/genética , Neutropenia/genética , Periodontite/genética , Periodontite/cirurgia , Extração Dentária/efeitos adversos , Adolescente , Éxons , Feminino , Humanos , Contagem de Leucócitos , Mutação , Neutropenia/sangue , Neutropenia/complicações , Neutrófilos , Periodontite/sangue
8.
Anticancer Res ; 39(9): 4925-4931, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31519597

RESUMO

BACKGROUND/AIM: Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy where antioxidant enzyme peroxiredoxin 6 (Prx6) has previously been associated with adverse outcomes. Its systemic effects in DLBCL are unknown. MATERIALS AND METHODS: This study included 53 patients with DLBCL, five patients with primary central nervous system lymphoma (PCNSL) and 20 healthy controls. The expression of Prx6 was evaluated immunohistochemically in DLBCL tissue samples and compared to its expression in blood serum. RESULTS: Prx6 expression was the highest in healthy controls, followed by DLBCL patients and PCNSL patients. Febrile neutropenic infection after the first treatment course was associated with low pre-treatment Prx6 serum levels (<14 ng/ml) (p=0.025, OR=8.615, 95% confidence interval=1.032-71.933). Serum levels of Prx6 recovered after treatment (p=0.006). CONCLUSION: Patients with low Prx6 levels might be more prone to treatment-related adverse effects through elevated levels of oxidative stress.


Assuntos
/etiologia , Linfoma Difuso de Grandes Células B/sangue , Linfoma Difuso de Grandes Células B/complicações , Neutropenia/complicações , Neutropenia/etiologia , Peroxirredoxina VI/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Medição de Risco , Fatores de Risco
9.
Pharm. pract. (Granada, Internet) ; 17(3): 0-0, jul.-sept. 2019. tab, graf
Artigo em Inglês | IBECS | ID: ibc-188126

RESUMO

Background: Studies examining relationships between patient-related factors and treatment outcome in patients with candidemia are limited and often based on all-cause mortality. Objective: Our purpose was to examine the impact of concurrent renal replacement therapy (RRT) and other pre-specified factors on treatment outcome among adults with candidemia. Methods: This Institutional Review Board (IRB)-approved, single-center, case-cohort study included patients over 18 years of age admitted to Duke University Hospital between Jun 1, 2013 and Jun 1, 2017 with a blood culture positive for Candida spp. Treatment-, patient-, and disease-specific data were collected, and outcome (success/failure) determined 90 days after the index culture. An odds ratio (OR) and 95% confidence interval (95%CI) were calculated for the following during therapy: receipt of RRT, fluconazole monotherapy regimen, intensive care unit (ICU) stay, and neutropenia. Results: Among the 112 encounters (from 110 unique patients) included, treatment failure occurred in 8/112 (7.1%). Demographics were comparable between outcome groups. Among 12 patients receiving concomitant RRT, only 1 patient failed therapy. With regard to treatment failure, no significant differences were observed with RRT (OR, 1.21; 95%CI, 0.14 - 10.75), fluconazole monotherapy regimen (OR, 1.59; 95%CI, 0.3-8.27), ICU stay (OR, 1.43; 95%CI, 0.32-6.29), and neutropenia (0 treatment failures). Conclusions: Treatment failure, receipt of concomitant RRT, and neutropenia were infrequent in patients undergoing treatment for candidemia. In our cohort, exposure to RRT, a fluconazole monotherapy regimen, ICU stay, or neutropenia during treatment did not impact treatment outcome


Resumen en ingles


Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Candida/patogenicidade , Candidíase/etiologia , Candidemia/epidemiologia , Terapia de Substituição Renal/efeitos adversos , Neutropenia/complicações , Fatores de Risco , Fluconazol/uso terapêutico , Antifúngicos/uso terapêutico , Unidades de Terapia Intensiva/estatística & dados numéricos , Estudos Retrospectivos
10.
BMC Res Notes ; 12(1): 464, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362783

RESUMO

OBJECTIVE: The aim of this study was to determine the predominant bacterial species causing bacteremia among febrile cancer patients, and their antibacterial resistance profiles at the Uganda Cancer Institute. RESULTS: We enrolled in-patients with a documented fever (≥ 37.5 °C). Bacteria from positive blood cultures were identified using standard methods biochemically. Antibacterial susceptibility testing was performed with the Kirby-Bauer disc diffusion method. From a total of 170 febrile episodes, positive blood cultures were obtained from 24 (14.1%). A positive culture was more likely to be obtained from a patient with neutropenia (P = 0.017). Of 22 (66.7%) Gram-negative bacteria isolated, half were E. coli (n = 11). Gram-negative compared to Gram-positive bacteria were most likely to be isolated from patients with a hematologic malignancy (P = 0.02) or patients with neutropenia (P = 0.006). Of the isolated Enterobacteriaceae 85% (n = 20) were resistant to three or more classes of antibiotic and 41% (n = 7) had extended spectrum beta-lactamases. Of the 11 Gram-positive bacteria isolated, the S. aureus isolate was methicillin resistant but susceptible to vancomycin. Multidrug resistant Gram-negative bacteria are the main cause of bacteremia in febrile cancer patients at the Uganda Cancer Institute. There is need for ongoing microbial surveillance, infection prevention and control, and antibiotic stewardship programs.


Assuntos
Bacteriemia/microbiologia , Febre/microbiologia , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Positivas/microbiologia , Neoplasias/microbiologia , Neutropenia/microbiologia , Adulto , Antibacterianos/uso terapêutico , Bacteriemia/complicações , Bacteriemia/tratamento farmacológico , Bacteriemia/patologia , Hemocultura , Criança , Estudos Transversais , Farmacorresistência Bacteriana Múltipla/genética , Feminino , Febre/complicações , Febre/tratamento farmacológico , Febre/patologia , Expressão Gênica , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/enzimologia , Bactérias Gram-Negativas/genética , Infecções por Bactérias Gram-Negativas/complicações , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/patologia , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/enzimologia , Bactérias Gram-Positivas/genética , Infecções por Bactérias Gram-Positivas/complicações , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/patologia , Humanos , Masculino , Testes de Sensibilidade Microbiana , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neutropenia/complicações , Neutropenia/tratamento farmacológico , Neutropenia/patologia , Uganda , beta-Lactamases/genética , beta-Lactamases/metabolismo
11.
Medicine (Baltimore) ; 98(35): e16993, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31464949

RESUMO

RATIONALE: Parvovirus B19 (PV) infection is usually symptomless and can cause benign, short-lived conditions. Anemia associated with PRCA is the most representative hematologic manifestation, but neutropenia and thrombocytopenia have been rarely reported. PATIENT CONCERNS: Three patients were admitted to the hospital with neutropenia and thrombocytopenia. The accompanying symptoms were fever, myalgia, rash, or arthralgia, and all patients were previously healthy. DIAGNOSIS: Patients were positive for PV PCR and diagnosed with PV infection. Before the diagnosis of PV infection, 2 patients underwent BM study and almost absence of erythroid progenitor cells in BM aspiration were a clue for the PV infection. Other BM findings were hypocellular marrow and a few hemophagocytic histiocytes. INTERVENTIONS: Patients received supportive care with follow-up of CBC. OUTCOMES: All 3 patients spontaneously recovered from neutropenia and thrombocytopenia within 3 weeks without severe complications. LESSONS: The evaluation of PV infection should be considered in situations where there is neutropenia and thrombocytopenia in healthy individuals even without anemia as a differential diagnosis.


Assuntos
Neutropenia/complicações , Infecções por Parvoviridae/complicações , Infecções por Parvoviridae/diagnóstico , Trombocitopenia/complicações , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Parvoviridae/virologia , Parvovirus B19 Humano , Reação em Cadeia da Polimerase
12.
Ann Hematol ; 98(10): 2311-2318, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432214

RESUMO

The role of adjunctive corticosteroid in septic shock remains debatable, and its role has not been assessed in neutropenic patients. We evaluated whether hydrocortisone reduces 28-day mortality in neutropenic patients with septic shock. We conducted a retrospective cohort study between January 2012 and May 2017 at a tertiary care center in South Korea. Patients who developed septic shock treated with at least one vasopressor and whose absolute neutrophil count was < 1000 cells/µL were included. Patients were classified into a steroid and a no-steroid group. The primary outcome of the study was 28-day mortality. Propensity score matching was used to adjust baseline characteristics and disease severity between the groups. Of the 287 patients analyzed, 189 were classified in the no-steroid group and 98 in the steroid group. Fifty propensity score-matched pairs were compared for the study outcomes. We found no significant difference in 28-day mortality between patients treated with and without steroid after propensity score matching (38.0% and 42.0%, respectively; p = 0.838). Incidences of pneumonia and gastrointestinal bleeding were more frequent in the steroid group, but it was not statistically significant after matching. In conclusion, adjunctive hydrocortisone was not associated with reduced 28-day mortality in neutropenic patients with septic shock.


Assuntos
Hidrocortisona/administração & dosagem , Neutropenia , Choque Séptico , Adulto , Idoso , Feminino , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/mortalidade , Humanos , Hidrocortisona/efeitos adversos , Incidência , Masculino , Pessoa de Meia-Idade , Mortalidade , Neutropenia/complicações , Neutropenia/tratamento farmacológico , Neutropenia/mortalidade , Pneumonia/etiologia , Pneumonia/mortalidade , Estudos Retrospectivos , Choque Séptico/complicações , Choque Séptico/tratamento farmacológico , Choque Séptico/mortalidade , Fatores de Tempo
13.
Am J Case Rep ; 20: 1027-1034, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31308356

RESUMO

BACKGROUND Theranostics is a combined diagnostic and treatment approach to individualized patient care. Kostmann syndrome, or severe congenital neutropenia, is an autosomal recessive disease that affects the production of neutrophils. Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy associated with gene alterations, including in the mitogen-activated protein kinase (MAPK) signaling pathway gene. Translocation of the ETS variant 6/neurotrophic receptor tyrosine kinase 3 (ETV6/NTRK3) gene has been implicated in radiation-induced and pediatric forms of thyroid carcinoma but has rarely been described in sporadic PTC. This report is of a case of PTC in a patient with Kostmann syndrome associated with ETV6/NTRK3 gene translocation. CASE REPORT A 32-year-old woman with a history of Kostmann syndrome, acute myeloid leukemia (AML), and chronic graft versus host disease (GVHD) was diagnosed with PTC with cervical lymph node metastases and soft tissue invasion following total thyroidectomy and bilateral modified radical neck dissection. Her postoperative radioactive iodine (RAI) scan confirmed lymph node metastasis. Gene expression studies identified increased expression of iodine-handling genes and ETV6/NTRK3 gene fusion. Because of the bone marrow compromise due to Kostmann syndrome and AML, a careful genomic and molecular analysis was performed to guide therapy. CONCLUSIONS This is the first reported case of the association between PTC, Kostmann syndrome, and ETV6/NTRK3 gene translocation in which multimodality treatment planning was optimized by genomic profiling.


Assuntos
/terapia , Neutropenia/congênito , Nanomedicina Teranóstica , Câncer Papilífero da Tireoide/terapia , Neoplasias da Glândula Tireoide/terapia , Adulto , /genética , Feminino , Fusão Gênica/genética , Humanos , Neutropenia/complicações , Neutropenia/genética , Neutropenia/terapia , Proteínas Proto-Oncogênicas c-ets/genética , Receptor trkC/genética , Proteínas Repressoras/genética , Câncer Papilífero da Tireoide/complicações , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/genética
14.
Infection ; 47(5): 837-845, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31187401

RESUMO

PURPOSE: The length of neutropenia has a significant impact on the incidence of bloodstream infection (BSI) in cancer patients, but limited information is available about the pathogen distribution in late BSI. METHODS: Between 2002 and 2014, BSI episodes in patients with neutropenia receiving chemotherapy for hematologic malignancies were prospectively identified by multicenter, active surveillance in Germany, Switzerland and Austria. The incidence of first BSI episodes, their microbiology and time to BSI onset during the first episode of neutropenia of 15,988 patients are described. RESULTS: The incidence rate of BSI episodes was 14.7, 8.7, and 4.7 per 1000 patient-days in the first, second, and third week of neutropenia, respectively. BSI developed after a median of 5 days of neutropenia (interquartile range [IQR] 3-10 days). The medium duration of neutropenia to BSI onset was 4 days in Escherichia coli (IQR 3-7 days), Klebsiella spp. (2-8 days), and Staphylococcus aureus (3-6 days). In contrast, BSI due to Enterococcus faecium occurred after a median of 9 days (IQR 6-14 days; p < 0.001 vs. other BSI). Late onset of BSI (occurring after the first week of neutropenia) was also observed for Stenotrophomonas maltophilia (12 days, IQR 7-17 days; p < 0.001), and non-albicans Candida spp. (13 days, IQR 8-19 days; p < 0.001). CONCLUSIONS: Over the course of neutropenia, the proportion of difficult to treat pathogens such as E. faecium, S. maltophilia, and Candida spp. increased. Among other factors, prior duration of neutropenia may help to guide empiric antimicrobial treatment in febrile neutropenia.


Assuntos
Antineoplásicos/efeitos adversos , Bacteriemia/tratamento farmacológico , Bacteriemia/etiologia , Infecção Hospitalar/epidemiologia , Neoplasias Hematológicas/complicações , Neutropenia/complicações , Adulto , Antibacterianos/uso terapêutico , Antineoplásicos/uso terapêutico , Áustria/epidemiologia , Bacteriemia/epidemiologia , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/microbiologia , Monitoramento Epidemiológico , Feminino , Alemanha/epidemiologia , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/epidemiologia , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/epidemiologia , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Estudos Retrospectivos , Infecções Estafilocócicas/tratamento farmacológico , Suíça/epidemiologia
15.
Mycoses ; 62(9): 847-853, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31166627

RESUMO

Fungal cholecystitis is an uncommon entity, and no cases of cholecystitis associated with mould infection have been reported. We present a case of acute Fusarium cholecystitis in a cytopenic patient with leukaemia who had disseminated fusariosis. We also review the published cases of fungal cholecystitis, which is most often caused by Candida species. Although it is rare, fungal cholecystitis should be part of the differential diagnosis of acute cholecystitis in high-risk patients with predisposing factors for opportunistic fungal infections.


Assuntos
Colecistite Acalculosa/diagnóstico , Colecistite Acalculosa/microbiologia , Colecistite Aguda/microbiologia , Infecções Oportunistas/diagnóstico , Abdome/diagnóstico por imagem , Colecistite Acalculosa/tratamento farmacológico , Adulto , Antifúngicos/uso terapêutico , Biópsia , Diagnóstico Diferencial , Feminino , Fusariose/tratamento farmacológico , Fusariose/microbiologia , Fusarium/patogenicidade , Humanos , Pulmão/diagnóstico por imagem , Neutropenia/complicações , Neutropenia/microbiologia , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/microbiologia , Pele/microbiologia , Pele/patologia , Tomografia Computadorizada por Raios X , Resultado do Tratamento
16.
J Mycol Med ; 29(3): 278-281, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31202517

RESUMO

Saprochaete clavata and Saprochaete capitata are closely related fungal species (family Dipodascaceae, order Saccharomycetales) that are rarely involved in the etiology of systemic infections in humans. In recent years, these yeasts are emerging as cause of life-threatening infections in patients with severe neutropenia and haematological malignancies. Infections by these fungi have been reported mostly from Mediterranean countries. To the best of our knowledge, only 2 cases of infection due to S. capitata have been reported in solid organ transplant recipients and none due to S. clavata. Herein we report a fatal case of S. clavata disseminated infection occurring in a patient with recent kidney transplantation and severe neutropenia. Patient was receiving antifungal echinocandin prophylaxis and the yeast was isolated from the blood and multiple non contiguous sites. Saprochaete spp. should be considered in the differential diagnosis of invasive mycoses in transplant recipients, especially if they are neutropenic and living or travelling in Mediterranean countries.


Assuntos
Infecções Fúngicas Invasivas/diagnóstico , Transplante de Rim , Saccharomycetales/isolamento & purificação , Transplantados , Antifúngicos/administração & dosagem , Diagnóstico Diferencial , Equinocandinas/administração & dosagem , Evolução Fatal , Feminino , Fungemia , Humanos , Infecções Fúngicas Invasivas/sangue , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Neutropenia/complicações , Neutropenia/microbiologia
17.
Breast Cancer ; 26(5): 637-650, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31127500

RESUMO

BACKGROUND: The cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib, in combination with endocrine therapy (ET), significantly prolonged progression-free survival in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC) in PALOMA-2 and PALOMA-3. Neutropenia and palbociclib dose reductions/interruptions occurred more frequently in the Japanese versus overall populations. We evaluated neutropenia patterns, palbociclib dose management, and clinical responses after dose reduction in Japanese patients in PALOMA-2 and PALOMA-3 and a single-arm Japanese phase 2 study. METHODS: PALOMA-2 and the Japanese phase 2 study enrolled postmenopausal women with estrogen receptor-positive, HER2- ABC who had not received prior systemic therapy for advanced disease; PALOMA-3 enrolled women with HR+/HER2- ABC, regardless of menopausal status, whose disease had progressed after prior ET. Palbociclib (125 mg/day) was administered 3 weeks on/1 week off. Dose reduction/interruption, cycle delay, tumor response, and laboratory-assessed neutropenia were analyzed in Japanese patients who received palbociclib. RESULTS: A total of 101 Japanese patients received palbociclib + ET. Among Japanese patients in the 3 studies, the frequency of all-grade/grade 3/grade 4 neutropenia was 94%/53%/34%, 100%/69%/21%, and 100%/67%/26%, respectively. Twenty (63%), 28 (67%), and 15 (56%) patients required palbociclib dose reduction. Dose interruption or reduction did not affect palbociclib treatment duration, and durable tumor response was observed despite dose reduction. CONCLUSION: Neutropenia was manageable with dose modifications, without affecting palbociclib treatment duration or efficacy. TRIAL REGISTRATION: Pfizer (NCT01740427, NCT01684215, NCT01942135).


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neutropenia/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/complicações , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Terapia de Reposição Hormonal , Humanos , Japão , Menopausa , Pessoa de Meia-Idade , Neutropenia/complicações , Neutrófilos/metabolismo , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Resultado do Tratamento
18.
Mycoses ; 62(8): 651-658, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31066092

RESUMO

Invasive aspergillosis (IA) is a serious hazard to haematological and critical care patients. Impactful risk factors for developing IA have been characterised; however, systematic analysis of baseline prognostic factors for treatment course of IA is missing. To understand prognostic variables, we analysed original articles identifying baseline factors that predict treatment outcome in patients with IA. PubMed database was searched for publications since database inception until May 2018. Inclusion criteria were published baseline prognostic factors present at the diagnosis of IA. In total, 58 studies from 267 centres reported 7320 patients with IA and 40 different predictors. Unfavourable predictors in medical history were kidney (7.4%, 10/136) and liver failure (3.7%, 5/136), ICU admission (3.7%, 5/136) and uncontrolled underlying disease (3.7%, 5/136). Regarding state of immunosuppression, negative outcome predictors were prolonged neutropenia (12.5%, 17/136), corticosteroid treatment (8.1%, 11/136) and graft-vs-host disease (3.7%, 5/136). On the pathogen side, relevant predictors were galactomannan positivity (8.1%, 11/136), Aspergillus terreus infection (2.2%, 3/136) and lack of amphotericin B susceptibility (1.5%, 2/136). IA-specific predictors were disseminated disease (5.1%, 7/136) and CNS involvement (2.9%, 4/136). Imaging results associated with negative outcome were multiple consolidations (2.9%, 4/136), bipulmonary lesions (2.2%, 3/136) and pleural effusion (2.2%, 3/136). At diagnosis of IA, most frequently identified predictors of outcome were neutropenia, corticosteroid use, elevated galactomannan, renal failure and disseminated disease. The predictors may be used to identify patients at high risk for treatment failure and to stratify neglected patient groups for clinical trials.


Assuntos
Aspergillus/patogenicidade , Aspergilose Pulmonar Invasiva/diagnóstico , Adulto , Antifúngicos/uso terapêutico , Doença Enxerto-Hospedeiro/complicações , Humanos , Imunossupressão/efeitos adversos , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Mananas/metabolismo , Neutropenia/complicações , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Falha de Tratamento , Resultado do Tratamento
19.
Pediatr Rheumatol Online J ; 17(1): 19, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31046790

RESUMO

BACKGROUND: CANDLE syndrome (an acronym for Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature) is a recently described rare autosomal recessive disorder charaterized by systemic autoinflammation. Clinical manifestations include presentation in the first year of life, episodes of fever accompanied by erythematous skin lesions, progressive lipodystrophy, violaceous periorbital swelling and failure to thrive. This syndrome is caused by loss of function mutations and malfunction of the immunoproteasome complex. Most patients have biallelic mutations in the PSMB8 gene that encodes the ß5i catalytic subunit of the immunoproteasome. Examples of digenic inheritance have been also described in CANDLE. CANDLE patients have strong type I interferon gene expression signature and they are responsive to treatment with JAK inhibitors. However, possible serious side-effects remain a concern. Here, we report another patient with CANDLE whose disease activity was well controlled by the treatment with baricitinib. CASE PRESENTATION: We report a Bulgarian patient of the Turkish ancestry who carries biallelic mutations in the PSMB8 gene: p.Ala92Val and p.Lys105Gln. The pathogenic variant p.Ala92Val has not been previously described in patients with CANDLE. We also comment on the unusual feature in this patient, nephrolithiasis, that has not been described in other patients, however it might be related to the positive family history for kidney stones. We have treated the patient with the JAK inhibitor baricitinib for the past year and we observed a significant amelioration of his inflammatory episodes, skin and joint manifestations, and improvements in physical activities and growth. The treatment with glucocorticoids (GC) was completely discontinued. No side effects have been observed, however they remain in consideration for a life-long therapy of this disease. CONCLUSIONS: CANDLE should be suspected in patients with early-onset systemic inflammatory disease and prominent skin manifestations. Molecular testing can confirm the clinical diagnosis and is very important in guiding therapies. Treatment with JAK inhibitors is highly efficacious and appears to be safe in children with CANDLE and other intereforonopathies.


Assuntos
Azetidinas/uso terapêutico , Dermatite/tratamento farmacológico , Febre/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Lipodistrofia/tratamento farmacológico , Neutropenia/tratamento farmacológico , Sulfonamidas/uso terapêutico , Doenças Autoimunes/complicações , Doenças Autoimunes/tratamento farmacológico , Criança , Doença Crônica , Dermatite/complicações , Febre/complicações , Humanos , Lipodistrofia/complicações , Masculino , Neutropenia/complicações , Complexo de Endopeptidases do Proteassoma/imunologia , Síndrome , Resultado do Tratamento
20.
J Pediatr Hematol Oncol ; 41(5): 345-354, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30973485

RESUMO

Invasive fungal infections (IFIs) are an important cause of morbidity and mortality in children with cancer. An overview of studies on the frequency and determinants of IFI in pediatric oncology patients in nonallogeneic stem cell transplantation settings is lacking. We performed a literature review in Pubmed and Embase, and included 13 prospective and 23 retrospective studies. The IFI frequency (proven/probable based on EORTC criteria) in nonallogeneic stem cell transplantation pediatric cancer patients ranged between 1.0% and 38.0%, with the highest frequencies reported in hematologic malignancies. The most common fungal species seen in the studied population was Candida, followed by Aspergillus. IFI are not well investigated in solid tumor patients. Significant recurrent determinants from univariate analysis were the diagnosis acute myeloid leukemia, (prolonged) neutropenia and an older age (above 10 years). The only 2 significant determinants based on multivariate analysis were the preceding number of days of broad-spectrum antibiotics (odds ratio, 1.05; 95% confidence interval, 1.02-1.07; P=0.0006) and the number of days of corticosteroids (odds ratio, 1.05; 95% confidence interval, 1.02-1.09; P=0.005), that were both based on a group of acute myeloid leukemia patients only. Future studies are necessary to determine the frequency and determinants of IFI in pediatric oncology including a representative number of solid tumor patients.


Assuntos
Neoplasias Hematológicas/complicações , Transplante de Células-Tronco Hematopoéticas/métodos , Infecções Fúngicas Invasivas/etiologia , Neoplasias/complicações , Adolescente , Corticosteroides/efeitos adversos , Fatores Etários , Antibacterianos/efeitos adversos , Aspergillus/patogenicidade , Candida/patogenicidade , Criança , Neoplasias Hematológicas/microbiologia , Humanos , Infecções Fúngicas Invasivas/epidemiologia , Leucemia Mieloide Aguda/complicações , Neoplasias/microbiologia , Neutropenia/complicações , Fatores de Risco
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